A phase 3 multicenter, prospective, open-label efficacy and safety study of immune globulin (human) 10% caprylate/chromatography purified in patients with myasthenia gravis exacerbations

Background: Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular transmission. Exacerbations may involve increasing bulbar weakness and/or sudden respiratory failure, both of which can be critically disabling. Management of MG exacerbations includes plasma exchange and intravenous immunoglobulin (IVIG); they are equally effective, but patients experience fewer side effects with IVIG. The objective of this study was to assess the efficacy and safety of immune globulin caprylate/chromatography purified (IGIV-C) in subjects with MG exacerbations. Methods: This prospective, open-label, non-controlled 28-day clinical trial was conducted in adults with MG Foundation of America class IVb or V status. Subjects received IGIV-C 2 g/kg over 2 consecutive days (1 g/kg/day) and were assessed for efficacy/safety on Days 7, 14, 21, and 28. The primary efficacy endpoint was the change from Baseline in quantitative MG (QMG) score to Day 14. Secondary endpoints of clinical response, Baseline to Day 14, included at least a 3-point decrease in QMG and MG Composite and a 2-point decrease in MG-activities of daily living (MG-ADL). Results: Forty-nine subjects enrolled. The change in QMG score at Day 14 was significant (p < 0.001) in the Evaluable (-6.4, n = 43) and Safety (-6.7, n = 49) populations. Among evaluable subjects, Day 14 response rates were 77, 86, and 88% for QMG, MG Composite, and MG-ADL, respectively. IGIV-C showed good tolerability with no serious adverse events. Conclusions: The results of this study show that IGIV-C was effective, safe, and well tolerated in the treatment of MG exacerbations

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

The Pliocene Ixtacamaxtitlan low sulfidation epithermal deposit (Puebla, Mexico A case of fossil fungi consortia in a steam-heated environment

The Ntacamaxtithin area in northern Puebla (central Mexico) contains middle Miocene Cu-Mo-Au porphyry/skarn and Pliocene low-sulfidation Au-Ag epithermal deposits that are geologically associated with the evolution of the Timis-Mexican Volcanic Belt (TATVB). In this paper, a new Ar-40/Ar-39 age (2.87 +/- 0.41 Ma) is provided for rhombohedral alunite from a kaolinite + alunite +/- opal +/- cristobalite +/- sin ectite advanced argillic alteration assemblage. This age contributes to the definition of a metallogenic province that is confined to the TIVIVB, a relevant feature for regional exploration. A similar to 12 My gap is established between the formation of the Cu-Mo-Au porphyry/ skarn and low-sulfidation Au-Ag epithermal deposits, which rules out the possibility that their overlapping was the result of telescoping Advanced argillic alteration is conspicuous throughout the mineralized area. This alteration assemblage consists of a widespread kaolinite-rich blanket that underlies silica sinters, polymictic hydrothermal breccias, and an alunite-rich spongy layer that consists of vertical tubular structures that are interpreted as the result of gas venting in a subaerial environment. The above indicate a shallow hypogene origin for the advanced argillic alteration assemblage that is, formation by the partial condensation within a phreatic paleoaquifer of acidic vapors that were boiled-off along fractures that host epithermal veins at depth. The formation of the spongy alunite layer and silica sinters is interpreted to have been synchronous. Within the alunite-rich spongy layer, tubular structures hosted microbial consortia dominated by fungi and possible prokaryote (Bacteria or Archaea) biofilms. Such consortia were developed on previously formed alunite and kaolinite and were preserved due to their replacement by opal, kaolinite, or alunite. This means that the proliferation of fungi and prokaryotes occurred during a lull in acidic gas venting during which other organisms (i.e., algae) might have also prospered. Periodic acidic gas venting is compatible with a multi-stage hydrothermal system with several boiling episodes, a feature typical of active geothermal systems and of low-sulfidation epithermal deposits. The microstructures, typical for fungi, are mycelia, hyphae with septa, anastornoses between branches, and cord-like groupings of hyphae. Possible evidence for skeletal remains of prokaryote biofilms is constituted by cobweb-like microstructures composed of <1 mu m thick interwoven filaments in close association with hyphae (about 2.5 pm thick). Bioweathering of previously precipitated minerals is shown by penetrative biobrecciation due to extensive dissolution of kaolinite by mycelia and by dissolution grooves from hyphae on alunite surfaces. Such bioweathering was possibly predated by inorganically driven partial dissolution of alunite, which suggests a lull in acidic gas venting that allowed living organisms to thrive. This interpretation is sustained by the occurrence of geometrical dissolution pits in alunite covered by hyphae. Fungal bioweathering is particularly aggressive on kaolinite due to its relatively poor nutrient potential. Such delicate microstructures are riot commonly preserved in the geological record. In addition, numerous chalcopyrite microcrystals or microaggregates are found within the alunite layer, which could be related to sulfate reduction due to bacterial activity from the sulfate previously released by fungal bioweathering of alunite. Iiydrogeochernical modeling constrains pH to between similar to 3.2 and similar to 3.6 and temperature to between 53 and 75 degrees C during the stage in which fungi and other organisms thrived. These waters were cooler and more alkaline than in earlier and later stages, which were characterized dominantly by steam-heated waters. The most likely process to account for this interlude would be mixing with meteoric water or with upwelling mature water that did not undergo boiling. El área de Ixtacamaxtitlán en el norte de Puebla (México central) contiene depósitos de tipo pórfido/ skarn de Cu-Mo-Au del Mioceno medio y depósitos epitermales de baja sulfuración de Au-Ag del Plioceno, que están geológicamente asociados a la evolución de la Faja Volcánica Trans-Mexicana (FVTM). En este trabajo se presenta una nueva edad 40Ar/39Ar (2.87 ± 0.41 Ma) en alunita romboédrica procedente de una asociación de alteración argílica avanzada constituida por kaolinita + alunita ± ópalo ± cristobalita ± esmectita. Esta edad contribuye a la definición de una provincia metalogenética circunscrita a la FVTM, lo cual constituye un rasgo relevante para la exploración regional. Se ha determinado un lapso de ~12 millones de años entre la formación de los depósitos de tipo pórfido/skarn de Cu-Mo-Au y los depósitos epitermales de baja sulfuración de Au-Ag, lo cual invalida la posibilidad de que la superposición existente entre dichos depósitos constituya un auténtico telescopaje, contrariamente a interpretaciones previas. Además, dentro de dicho lapso se produjo la formación de un estratovolcán en el área de estudio, que habría interferido en cualquier actividad hidrotermal existente. La asociación de alteración argílica avanzada es reconocible en un área extensa de la zona mineralizada. Dicha asociación consiste en un amplio cuerpo subhorizontal rico en kaolinita que subyace a sínteres silícicos, brechas hidrotermales polimícticas, y un horizonte de aspecto esponjoso rico en alunita que consiste en estructuras verticales tubulares que se interpretan en este trabajo como debidas al escape de gases en un ambiente subaéreo. Tales características son compatibles con un ambiente de formación hipogénico somero para la asociación de alteración argílica avanzada—esto es, formación en terrenos calentados por vapor derivados de la condensación parcial en un paleoacuífero freático de vapores ácidos generados por ebullición a lo largo de fracturas que eventualmente alojaron vetas epitermales en profundidad. Se interpreta que la formación del horizonte esponjoso de alunita y de los sínteres silícicos fue sincrónica. En el interior de las estructuras tubulares de alunita se desarrollaron consorcios dominados por hongos que también incluyen posibles biofilmes de procariontes (bacterias o arqueas). Dichos consorcios se desarrollaron sobre alunita y kaolinita previamente precipitadas, y fueron preservados debido a su reemplazamiento por ópalo, kaolinita o alunita. Ello conlleva que la proliferación de hongos y procariontes se produjo en periodos de pausa en la emanación de gases ácidos, durante los cuales otros organismos (i.e., algas) pudieron haber igualmente prosperado. Este rasgo es compatible con un sistema hidrotermal multiepisódico con diversas etapas con ebullición, lo cual concuerda con el ambiente de formación de los depósitos epitermales de baja sulfuración. Las microestructuras observadas típicas de hongos son micelios, hifas septadas, anastomosis entre ramificaciones, y agrupaciones de hifas en forma de cable o cordón. La posible evidencia de restos esqueléticos de biofilmes de procariontes la constituyen microestructuras semejantes a telarañas formadas por el entramado de filamentos con grosores <1 µm, que se encuentran íntimamente asociadas a hifas (éstas, con grosores del orden de ~2.5 µm). La biometeorización de minerales previamente precipitados se muestra en forma de biobrechificación penetrativa debida a la extensa disolución de kaolinita generada por micelios y por el desarrollo de surcos de disolución generados por hifas en la superficie de los cristales de alunita. Dicha biometeorización vino antecedida por la disolución parcial de la alunita, posiblemente de origen inorgánico, lo cual denota la instalación de un ambiente más benéfico (menos ácido) para el desarrollo de organismos vivos y, por tanto, de un periodo de pausa en la exhalación de gases. Dicha interpretación se argumenta con la presencia de mellas geométricas de disolución en alunita, cubiertas por hifas. La biometeorización fúngica es particularmente agresiva en kaolinita debido a su relativamente pobre potencial nutritivo. Estos tipos de microestructuras delicadas no se preservan habitualmente en el registro geológico. Asimismo, se encuentran numerosos microcristales y microagregados de calcopirita en el horizonte de alunita, que pueden ser hipotéticamente asociados a reducción de sulfatos debida a actividad bacteriana, a partir del sulfato previamente liberado por medio de la biometeorización de alunita. El modelado hidrogeoquímico permitió constreñir el pH entre ~3.2 y ~3.6 y la temperatura entre 53° and 75 °C durante el estadio en que los hongos y otros organismos prosperaron en asociación con aguas más frías y alcalinas que en los estadios precedente y posterior, que se caracterizaron por la presencia dominante de aguas calentadas por vapor. Tales variaciones en temperatura y pH con respecto a los fluidos precedentes pudieron haber sido consecuencia de la mezcla entre éstos y otros fluidos de nueva incorporación. Los candidatos más verosímiles para permitir dicho interludio serían el agua meteórica o agua ascendente madura que no experimentó ebullición

The PEG13-DMR and brain-specific enhancers dictate imprinted expression within the 8q24 intellectual disability risk locus

Background: Genomic imprinting is the epigenetic marking of genes that results in parent-of-origin monoallelic expression. Most imprinted domains are associated with differentially DNA methylated regions (DMRs) that originate in the gametes, and are maintained in somatic tissues after fertilization. This allelic methylation profile is associated with a plethora of histone tail modifications that orchestrates higher order chromatin interactions. The mouse chromosome 15 imprinted cluster contains multiple brain-specific maternally expressed transcripts including Ago2, Chrac1, Trappc9 and Kcnk9 and a paternally expressed gene, Peg13. The promoter of Peg13 is methylated on the maternal allele and is the sole DMR within the locus. To determine the extent of imprinting within the human orthologous region on chromosome 8q24, a region associated with autosomal recessive intellectual disability, Birk-Barel mental retardation and dysmorphism syndrome, we have undertaken a systematic analysis of allelic expression and DNA methylation of genes mapping within an approximately 2 Mb region around TRAPPC9. Results: Utilizing allele-specific RT-PCR, bisulphite sequencing, chromatin immunoprecipitation and chromosome conformation capture (3C) we show the reciprocal expression of the novel, paternally expressed, PEG13 non-coding RNA and maternally expressed KCNK9 genes in brain, and the biallelic expression of flanking transcripts in a range of tissues. We identify a tandem-repeat region overlapping the PEG13 transcript that is methylated on the maternal allele, which binds CTCF-cohesin in chromatin immunoprecipitation experiments and possesses enhancer-blocker activity. Using 3C, we identify mutually exclusive approximately 58 and 500 kb chromatin loops in adult frontal cortex between a novel brain-specific enhancer, marked by H3K4me1 and H3K27ac, with the KCNK9 and PEG13 promoters which we propose regulates brain-specific expression. Conclusions: We have characterised the molecular mechanism responsible for reciprocal allelic expression of the PEG13 and KCNK9 transcripts. Therefore, our observations may have important implications for identifying the cause of intellectual disabilities associated with the 8q24 locus. © 2014 Court et al.; licensee BioMed Central Ltd

Role of Oral Nutritional Supplements Enriched with β-Hydroxy-β-Methylbutyrate in Maintaining Muscle Function and Improving Clinical Outcomes in Various Clinical Settings.

Aging and disease-related malnutrition are well associated with loss of muscle mass and function. Muscle mass loss may lead to increased health complications and associated increase in health care costs, especially in hospitalized individuals. High protein oral nutritional supplements enriched with β-hydroxy-β-methylbutyrate (HP-ONS+HMB) have been suggested to provide benefits such as improving body composition, maintaining muscle mass and function and even decreasing mortality rates. The present review aimed to examine current evidence on the effect of HP-ONS+HMB on muscle-related clinical outcomes both in community and peri-hospitalization patients. Overall, current evidence suggests that therapeutic nutrition such as HP-ONS+HMB seems to be a promising tool to mitigate the decline in muscle mass and preserve muscle function, especially during hospital rehabilitation and recovery

Prospective comparative multi-centre study on imported Plasmodium ovale wallikeri and Plasmodium ovale curtisi infections

BACKGROUND: Few previous retrospective studies suggest that Plasmodium ovale wallikeri seems to have a longer latency period and produces deeper thrombocytopaenia than Plasmodium ovale curtisi. Prospective studies were warranted to better assess interspecies differences. METHODS: Patients with imported P. ovale spp. infection diagnosed by thick or thin film, rapid diagnostic test (RDT) or polymerase chain reaction (PCR) were recruited between March 2014 and May 2017. All were confirmed by DNA isolation and classified as P. o. curtisi or P. o. wallikeri using partial sequencing of the ssrRNA gene. Epidemiological, analytical and clinical differences were analysed by statistical methods. RESULTS: A total of 79 samples (35 P. o. curtisi and 44 P. o. wallikeri) were correctly genotyped. Males predominate in wallikeri group (72.7%), whereas were 48.6% in curtisi group. Conversely, 74.3% of curtisi group were from patients of African ethnicity, whilst 52.3% of Caucasians were infected by P. o. wallikeri. After performing a multivariate analysis, more thrombocytopaenic patients (p = 0.022), a lower number of platelets (p = 0.015), a higher INR value (p = 0.041), and shorter latency in Caucasians (p = 0.034) were significantly seen in P. o. wallikeri. RDT sensitivity was 26.1% in P. o. curtisi and 42.4% in P. o. wallikeri. Nearly 20% of both species were diagnosed only by PCR. Total bilirubin over 3 mg/dL was found in three wallikeri cases. Two patients with curtisi infection had haemoglobin under 7 g/dL, one of them also with icterus. A wallikeri patient suffered from haemophagocytosis. Chemoprophylaxis failed in 14.8% and 35% of curtisi and wallikeri patients, respectively. All treated patients with various anti-malarials which included artesunate recovered. Diabetes mellitus was described in 5 patients (6.32%), 4 patients of wallikeri group and 1 curtisi. CONCLUSIONS: Imported P. o. wallikeri infection may be more frequent in males and Caucasians. Malaria caused by P. o. wallikeri produces more thrombocytopaenia, a higher INR and shorter latency in Caucasians and suggests a more pathogenic species. Severe cases can be seen in both species. Chemoprophylaxis seems less effective in P. ovale spp. infection than in P. falciparum, but any anti-malarial drug is effective as initial treatment. Diabetes mellitus could be a risk factor for P. ovale spp. infection